Comparing Cytokine Data To In-Life Parameters On Nonhuman Primates In Nonclinical Toxicology Studies

By Vivienne Bunker, Christopher Do, and Julie Forget

Cytokines are critical immunoregulatory proteins that play a key role in assessing innate and adaptive immune responses in safety evaluations. However, interpreting cytokine data presents challenges due to the variability of their stimuli and responses. Factors contributing to this variability include species-specific reactions, individual differences, dose-response relationships, and unexpected immunotoxicity. As a result, cytokine measurements should not be used as standalone biomarkers for immunotoxicity assessment. Instead, when evaluated alongside clinical observations, body weights, and clinical pathology data, cytokine analysis can provide a more comprehensive understanding of immune responses in nonclinical safety studies.

In several case studies, cytokines were analyzed for dose-response relationships using multiplex platforms such as Luminex and MSD®. These studies measured cytokines in nonhuman primates, including IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12/IL-23p40, MCP-1, IFN-γ, and TNF-α. In certain instances, measurable levels of IL-6 or IL-12 were correlated with clinical signs such as bruising, injury, or abnormal feces, though these effects were not necessarily test article-related. Elevated levels of TNF-α and IL-6, both pro-inflammatory cytokines, were detected in animals exhibiting dehydration, along with elevated BUN, creatinine, and decreased electrolytes. In test article-related cases, moribund animals also showed increased TNF-α and IL-6 levels. Additionally, increased MCP-1, a monocyte chemotactic factor, was observed in one study involving an animal with petechial bruising and another study where a cohort developed test article-associated renal failure, characterized by hypoproteinemia, azotemia, and hyperkalemia.

In conclusion, while cytokines are valuable markers in assessing potential toxicity, they should be interpreted in conjunction with other clinical measurements. Incorporating clinical observations, body weights, and clinical pathology data enhances the accuracy of toxicity assessments and strengthens the overall interpretation of immunotoxic effects in nonclinical studies.